Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035541 | SCV000059191 | uncertain significance | not specified | 2020-08-25 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala97Val variant in MYBPC3 has been reported in 1 individual with hypertrophic cardiomyopathy (Walsh 2017 PMID: 27532257, LMM data) but was absent from large population studies. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools predict a splicing impact through the creation of an alternate splice site which is in turn predicted to create a frameshift and premature termination and in vitro functional studies using a cell-based mini-gene splicing assay provide some evidence that this variant impacts splicing (Ito 2017 PMID: 28679633); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting. |
| Invitae | RCV000705202 | SCV000834188 | uncertain significance | Hypertrophic cardiomyopathy | 2021-08-12 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 97 of the MYBPC3 protein (p.Ala97Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant has been reported in individual(s) affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42670). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Blueprint Genetics | RCV000788839 | SCV000928101 | likely pathogenic | not provided | 2018-12-05 | criteria provided, single submitter | clinical testing |